Background: Severe psychiatric disorders, including bipolar disorder, are increasingly accepted as being induced by stress-related effects on neurobiology. A series of landmark studies have provided compelling evidence for a distinct role of FKBP5 – a key co-chaperone of the glucocorticoid receptor in response to stressors – in this process. The FKBP5 gene encodes a number of alternative transcripts, but these have not been characterized directly in the human brain despite the likelihood of tissue-specific transcriptional regulation of the FKBP5 gene. We thus aimed to identify FKBP5 alternative transcripts in human brain (anterior cingulate cortex and hippocampus) and to assess if alternative transcript levels are altered in bipolar disorder relative to matched psychiatrically healthy controls.

Methods: RNA sequencing was performed in the anterior cingulate cortex (BA24) and hippocampus of 13 healthy control and 13 bipolar disorder subjects (type I or type II), matched for age, freezer storage time, and brain pH. Sequencing was completed on the Illumina HiSeq2000 platform using 100-bp paired-end reads. Reads were aligned to the human genome reference (hg19) using TopHat, and Cufflinks was used to generate gene-level and isoform-level counts. Independent t-tests were used to assess differences in transcript expression in cases vs controls.

Results: Reads were mapped to six reported transcripts (variant 1-6) in both the anterior cingulate cortex and hippocampus in human brain. Confirmatory analyses of these variants are on-going. Analysis of the alternative transcripts revealed that, in both the anterior cingulate cortex and hippocampus, a truncated transcript of FKBP5 (variant 4) was significantly increased in bipolar disorder relative to controls (respectfully -66.39% and +35.76%). In the anterior cingulate cortex, variant 1 was also increased in bipolar patients (+70.33%), while variant 2 was decreased (-36.81%); these alterations were not seen in the hippocampus. The other variants were not altered in bipolar disorder compared to controls.

Conclusions: These data characterize FKBP5 alternative transcripts in two regions of the human brain highly implicated in the etiology of stress-induced psychiatric illnesses. In addition, we show that these transcripts are differentially altered in bipolar disorder, and that such alterations may vary according to brain region (i.e. anterior cingulate cortex vs hippocampus). Further analyses are now being conducted to verify the transcripts and their functional significance relevant to glucocorticoid-mediated stress signaling. In addition, these results are being integrated with evidence from other types of tissues to determine cross-tissue relevance.